Autonomic nervous system plays a pivotal role in controlling ocular functions

starting from aperture and focus control to the production of aqueous humour. It
also controls the intrinsic functions and blood supply to various ocular tissues
through cholinergic and adrenergic receptors. Cholinergic and adrenergic agonists
and antagonists are major class of drugs used in diagnostic and therapeutic
purposes in ophthalmology. This chapter is an attempt to review the autonomic
nervous system innervations to the ocular structures, their role in carrying out
physi- ological functions of eye and drugs acting through this system as
diagnostic, pallia- tive and curative strategies in various ophthalmic conditions.

Definisi

The structure of autonomic nervous system was morphologically explained by

Galen in AD 130–200. He described the presence of a “sixth cranial nerve” which
is currently known as ninth (glossopharyngeal) along with tenth (vagus) and elev-
enth (accessory nerves) and the sympathetic chain as well. He also exhibited the
presence of superior and inferior cervical ganglion, the semilunar ganglion, and
the rami communicantes which can be found in Traite des nerfs of Tissot in 1778
Ocular functions are highly influenced by the autonomic nervous system.
Functionally, they control the muscle responsible for pupillary diameter of the iris
(aperture control), muscles responsible for lens curvature (focus control), and
production of aqueous humor. Apart from this it also controls the blood sup- ply to
the iris, ciliary body, retina, choroid, and optic nerve. Trigeminal and auto- nomic
projections controlling ocular functions are shown in Fig. 6.1. The eye receives its
parasympathetic innervations through postganglionic ciliary gan- glion and
sympathetic innervations through superior cervical ganglion. Apart from this local,
intrinsic control has been achieved by trigeminal sensory fibers at many regions of
the eye and neurons within ciliary and pterygopalatine gan- glia at many regions
of the eye. The cornea is innervated by the sensory fibers of the trigeminal nerve
which is capable of stimulating lacrimation by the intercon- nections with the
lacrimal gland through pterygopalatine ganglia. Presence of endothelial alpha- and
beta-receptors in the cornea has been shown to modulate the corneal thickness by
their respective agonists (Nielsen and Nielsen 1985). Extensive information
regarding autonomic control of the eye can be read by the excellent review of
McDougal and Gamlin (2015) and Kardon (2005). Presence of cholinergic and
adrenergic receptors in various parts of the eye and their func- tional significance
are shown in Table 6.1.
Autonomic Control on the Pupil
Response –
Miosis

Contraction (near vision) Unknown

Secretion (3+) Unknown

Unknown

Increased resistance

Goblet cell secretion

Iris circular and radial muscles are innervated by postganglionic parasympathetic

and sympathetic nerves respectively. Upon the activation of sympathetic nerves,
nor- epinephrine is released from the postganglionic nerve ending, causing radial
mus- cles of the iris to get contracted, causing mydriasis, whereas parasympathetic
activation releases acetylcholine (ACh) from postganglionic nerve terminals
causing miosis. The mechanism of them causing mydriasis and miosis are shown
in Fig. 6.2. The dynamic equilibrium between both of the nervous systems
determines pupillary diameter based upon the amount of light reaching the retina.
The normal human eye can dilate the pupil from 1.5 to 8 mm in diameter and this
change is expected to modulate the depth of focus, optical aberration, retinal
illumination, and diffraction. Coordinated performance of the iris aperture along
with focal length adjustment rendered by ciliary muscles by autonomic control is
required for the optimum per- formance of visual system at different conditions.
When the dynamic equilibrium exists between the sympathetic and
parasympathetic system, pharmacological agents are used to achieve mydriasis or
miosis by stimulating the appropriate autonomic

162

N. Halder et al.

Constriction of radial muscles

Constriction of sphincter muscle

Mydriasis Sympathetic stimulation

Miosis Para-sympathetic stimulation

Fig. 6.2 Showing the effect of adrenergic (sympathetic) and cholinergic

(parasympathetic) stimu- lation on pupillary diameter causing mydriasis and miosis
respectively

receptors. Phenylephrine is an alpha-1 agonist capable of stimulating the

contraction of iris radial muscle and cause mydriasis but atropine which is a
muscarinic blocker is capable of removing the influence of cholinergic stimuli-
induced contraction on iris circular muscle (sphincter muscle), thereby causing the
domination of existing tone of sympathetic system leading to mydriasis.
Dapiprazole is a selective α(1)- adrenoreceptor antagonist approved to reverse the
mydriasis induced by atropine.

Similarly, miosis can be induced by the stimulation circular muscles of the iris
(sphincter muscle) using cholinomimetic-like pilocarpine or cholinesterase
inhibitors and α(1)-adrenoreceptor blocker dapiprazole. Dapiprazole causes miosis
by remov- ing the action of sympathetic tone on radial muscles of the iris, leading
to the shift of equilibrium to cholinergic tone (Bartlett and Classe 1992).

Apart from the presence of acetylcholine (neurotransmitter of cholinergic nerves)

and norepinephrine (neurotransmitter of sympathetic nerves), other neurotransmit-
ters and neuropeptides such as VIP, neuropeptide Y, nitric oxide synthase (for
nitric oxide), and ATP were identified in the postganglionic neurons; they are not
exploited so far by any pharmacological means for diagnostic or therapeutic
potential. However, they are reported to be involved in the intrinsic pathways in
controlling blood supply, aqueous humor dynamics, and other functions
(Neuhuber and Schrodl 2011). The list of adrenergic and cholinergic receptors
identified in various ocular structures and their functional importance are shown in
Table 6.1. Apart from the classical autonomic pathway, morphine is known to
stimulate parasympathetic pathway through the Edinger-Westphal nucleus,
causing miosis in the iris.

Anisocoria is a condition commonly manifested by the unequal sizes of pupils.

This could vary from simple to life-threatening conditions. Pupillary inequality is
usually identified by their reaction in both dim and bright illuminations before ini-
tiating further clinical proceedings. Once the dysfunctioning of pupils is
confirmed, differential diagnostic procedure is opted in neuro-ophthalmology in
defining the

6 Drugs Acting Through Autonomic System for Ocular Use 163

underlying condition. It is aided by a handful of drugs like pilocarpine, hydroxyl-

amphetamine, cocaine, phenylephrine, and morphine.

Autonomic Control Over Blood Circulation and

Neuroprotection
Alpha-2 adrenergic agonists, in addition to their pressure-lowering effects in the
eye, may act directly upon retinal neurons, including retinal ganglion cells. Alpha-
2A expression was identified in the human retina, on ganglion cells, and cells in
the inner and outer nuclear layers (Kalapesi et al. 2005), whereas only a few
clinical studies so far showed any benefit of neuroprotection in glaucoma (Evans
et al. 2003; Sena and Lindsley 2013). Presence and involvement of β-adrenergic
system in angiogenic pro- cesses has been implicated in infantile hemangiomas,
retinopathy of prematurity, and cancer (Filippi et al. 2015). As the
neurotransmitters of the autonomic nervous system such as acetylcholine and
norepinephrine are vasoactive substances, therefore, pres- ence of adrenergic and
cholinergic receptors at the cornea, iris, ciliary body, retina, and choroid is
expected to play a significant role on their vascular tone and cellular

6 Drugs Acting Through Autonomic System for Ocular Use 165

homeostasis (Mori et al. 2010; Toda et al. 1996; Casini et al. 2014). However, the
current knowledge available is not enough to speculate the pharmacological
utiliza- tion of these receptors in various ophthalmic conditions.

6.7 Drugs Acting Through Sympathetic Nervous System

Adrenergic agonists and antagonists are the major class of drugs which have been
extensively used in ophthalmology. Norepinephrine, epinephrine, and dopamine
are the three major adrenergic neurotransmitters of the sympathetic division of the
auto- nomic nervous system. These amines work by activating adrenergic
receptors, namely, alpha- and beta-receptors, present in various tissues of the eye
which are primarily innervated by postganglionic sympathetic nerves. The
distribution of these receptors is mentioned in Table 6.1.

Adrenergic agonists can be classified into directly acting, indirectly acting, and
mixed-acting agents. Drugs such as epinephrine which can directly stimulate the
receptors by binding to one or more receptors are known as directly acting. Drugs
which can increase the release of responsible neurotransmitter from presynaptic
vesicles to augment the effect of the sympathetic innervations are known as indi-
rectly acting such as cocaine. Drugs which can perform both the actions of direct
and indirect activation are known as mixed acting (Fig. 6.1).

The eye has both alpha- and beta-adrenergic receptors. Adrenergic receptors are
present in corneal epithelium, endothelium, iris radial and sphincter muscles, tra-
becular meshwork, ciliary epithelium, ciliary muscles, lacrimal gland, and retinal
pigment epithelium (Table 6.1). The adrenergic system plays a vital role in main-
taining the tonicity of this part for the physiological processes of the eye through
constriction and dilation. Thus, this system has been a subject for manipulation for
various diagnostic, palliative, and curative strategies in ophthalmic conditions.

6.7.3 Indirectly Acting Sympathomimetics

6.7.3.2 Cocaine
H3C N

O
O

O
O

CH3

Cocaine is produced from the leaves of the coca plant (Erythroxylum coca). It is
an ester of benzoic acid and methylecgonine. It is one of the directly acting
sympatho- mimetics used often for mydriasis and local anesthetic effect.

Mechanism of Action and Therapeutic Use

Cocaine inhibits the reuptake of the neurotransmitter, namely, norepinephrine,
dopamine, and serotonin, at postganglionic sympathetic nerve endings.
Accumulation of neurotransmitter at the synaptic cleft stimulates the adrenergic
receptors. When given topically in the eye, radial muscle of the pupil contracts and
causes mydriasis. Cocaine is used from a long time for the diagnosis of anisocoria
produced by Horner’s syndrome. Sympathetic innervation disturbance anywhere
will result in less or no neurotransmitter release at the synaptic cleft, and cocaine
in that case would not be able to produce mydriasis, which is a confirmation tool
for the aniso- coria that resulted from Horner’s syndrome (Smit 2010). Besides
this action, cocaine also inhibits the nerve impulses; thus it is also used as local
anesthetic.

Dosage

Cocaine is available in 1–4 % ophthalmic solution for the diagnosis of anisocoria

and for local anesthesia prior to ophthalmic surgeries such as lid surgery. Cocaine
2–10 % has been the gold standard in the diagnosis of unilateral Horner’s
syndrome for more than 30 years (Smit 2010).

Side Effects

Although no evident side effects have been seen for topically applied cocaine oph-
thalmic solution, systemic absorption can cause nervousness, excitement,
euphoria, confusion, agitation, and restlessness.

6.7.5 Alpha-2 Adrenergic Receptor Agonist

The α(2)-adrenergic receptors are predominantly present at the ciliary epithelium
where aqueous humor production takes place. Involvement of these receptors is
found to have an enormous importance in the treatment of ocular hypertension,
glaucoma, uveitis, strabismus, and several diagnostic purposes.

6.7.5.2 Apraclonidine

Apraclonidine, a para-amino derivative of clonidine, has shown low penetration

across the blood-brain barrier, thus minimizing cardiovascular and systemic side
effects. It stimulates α(2)-adrenergic receptors present on nonpigmented ciliary
epithelium which in turn leads to reduction of IOP (Gharagozloo et al. 1988).
Cl
NH

N HCl
HN

Mechanism of Action
H2N

Cl

Apraclonidine is a relatively selective agonist of prejunctional α(2)-adrenergic

receptors present on nonpigmented ciliary epithelium. It causes inhibition of
membrane-bound adenylate cyclase which in turn impairs the conversion of ATP
to c-AMP, thereby reducing production of aqueous humor (Gharagozloo et al.
1988). Vasoconstriction of arterioles also resulted in less ciliary body blood flow,
thus reducing aqueous production. It also influences the aqueous humor drainage
path- way which includes mostly the uveoscleral outflow, and in less instances,
conjunc- tival and episcleral vascular flow may also be involved (Hurvitz et al.
1991; Toris et al. 1995b).

Therapeutic Uses

Apraclonidine is approved for the treatment of elevated IOP in normotensive and

glaucomatous human eyes by suppressing the rate of aqueous production (Yüksel
et al. 1992). In a study, apraclonidine at 0.5 % was found to have better therapeu-
tic efficacy than 1 % ophthalmic solution in reducing IOP (Rosenberg et al. 1995).
It has been found useful as a short-term adjunctive therapy to timolol for the
poorly controlled glaucoma (Morrison and Robin 1989; Stewart et al. 1995). It has
been used as a diagnostic agent for Horner’s syndrome (Chen et al. 2006). It has
been reported that it is safe and effective as a single postoperative administra- tion
for reducing the elevated IOP after argon laser trabeculoplasty (Holmwood et al.
1992; Robin et al. 1987b), argon laser iridotomy (Hong et al. 1991; Robin

6 Drugs Acting Through Autonomic System for Ocular Use 175 et al. 1987a), and Nd-
YAG laser capsulotomy (Brown et al. 1988; Cullon and

Schwartz 1993; Pollack et al. 1988).

Dosage

Apraclonidine is available commercially at 0.5 and 1 %w/v ophthalmic solution. It

needs to be instilled one drop three times daily. Within 1 h post instillation, it pro-
duces 20 % reduction in IOP in the glaucomatous eye and maximum effect can be
seen at 3–5 h. Its duration of action for IOP reduction stays for 5–8 h. It is com-
monly administered as an adjunctive therapy to timolol for reducing IOP. It is
contraindicated in patients receiving monoamine oxidase (MAO) inhibitors or tri-
cyclic antidepressants.

Side Effects

Ocular side effects include photosensitivity, transient lid retraction, mydriasis, and
conjunctival blanching. Transitory Snellen acuity and allergic conjunctivitis are
the other side effects.

Apraclonidine modulates the effect of endogenous neurotransmitters through pre-

junctional and post-junctional a2-receptors and would be expected to cause
pupillary miosis in normal subjects (15,16). But it also has the ability to stimulate
a1-adrenergic receptors with a lower efficacy than norepinephrine (12). In a study
to determine its site of action in lowering intraocular pressure, apracloni- dine was
found to cause mydriasis in patients who had both glaucoma and Horner syndrome
(12). This effect was explained by denervation hypersensitivity to apraclonidine of
a1-receptors in the iris dilator muscles because of loss of normal sympathetic
innervation

Apraclonidine memodulasi efek neurotransmitter endogen melalui pra-junctional

dan pasca-junctional a2-receptors dan diharapkan untuk menyebabkan miosis pupil
pada subyek normal . Tetapi juga memiliki kemampuan untuk merangsang reseptor
a1-adrenergik dengan efikasi yang lebih rendah daripada norepinefrin (12). Dalam
sebuah penelitian untuk menentukan tempat kerjanya dalam menurunkan tekanan
intraokular, apracloni- dine ditemukan menyebabkan midriasis pada pasien yang
memiliki sindrom Horner . Efek ini dijelaskan oleh hipersensitivitas denervasi
terhadap apraclonidine reseptor a1 pada otot iris dilator karena hilangnya
persarafan simpatis yang normal.